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Weight loss and the brain: why it’s difficult to control our expanding waistlines

Losing weight and keeping it off can be hard due to hormonal changes. Colros

Welcome to part eight of The science behind weight loss, a Conversation series in which we separate the myths about dieting from the realities of exercise and nutrition. Here, Joseph Proietto, Professor of Medicine at the University of Melbourne, explains that once people become obese, their bodies are programmed to regain any weight they manage to lose:

The world is in the midst of an obesity epidemic that’s proving difficult to control. As a result, rates of type 2 diabetes, hypertension, heart disease and obstructive sleep apnoea continue to rise, along with social stigma directed at those who struggle to control their weight.

There is emerging evidence that obesity has a strong genetic basis (where a mutation changes the gene sequence and alters the production of protein) or epigenetic basis (where the sequence is normal but the expression or reading of the gene is altered).

We now know that once a certain genetically determined weight is reached, the body defends it vigorously. This means that although someone with clinical obesity can lose weight and keep it off for a year or two, the weight is likely to be regained in the longer term.

Food and the brain

To understand the physiological defence mechanism of body weight, we first need to review how the body regulates our food intake.

Weight is controlled in the hypothalamus, a small area at the base of the brain, located in the midline, behind the eyes. Within the hypothalamus are nerve cells that, when activated, produce the sensation of hunger.

Hypothalamus small
Red: the hypothalamus.

In close proximity to these cells is another set of nerves that, when activated, take our hunger away.

Our desire to eat, therefore, is determined by which of these two types of nerves dominate at a particular time.

So what controls the activity of these key (first order) nerve cells and decides which group prevails – and either makes us hungry or suppresses our hunger?

There appear to be at least 10 circulating hormones that can influence the desire to eat. Of these, six come from the gut (ghrelin, CCK, PYY, GLP-1, Oxyntomodulin and uroguanylin; one comes from fat (leptin); and three come from the pancreas (insulin, amylin and PP).

Only one of these makes us hungry (ghrelin, which comes from the gut). All the others have been shown to reduce hunger. (The consumption of glucose and fatty acids also reduce hunger.)

The nerves in the hypothalamus not only respond to these circulating hormones and nutrients, they also have other modulating inputs.

Once it’s full, the stomach reduces the desire to eat both by lowering ghrelin production (the hormone that makes us hungry), and by sending a message to the hypothalamus.

The hypothalamus also receives signals from pleasure pathways that use dopamine, endocannabinoids, and serotonin as messengers, which influence eating behaviour.

Controlling hunger

When someone loses weight through lifestyle changes, such as reduced calorie intake and increased physical activity, the levels of some of the hunger-controlling hormones change, making the individual want to eat more.

There is a reduction in leptin, CCK, PYY, GLP-1, amylin and insulin, while ghrelin levels rise. The net result is increased hunger and we have recently shown that these changes persist for over a year.

The body also becomes more “fuel efficient”, with energy expenditure decreasing by about 300 calories per day below the baseline.

So, to maintain weight loss, the individual must substantially increase their energy expenditure and fight the feeling of hunger. It’s not surprising that most give up.

It follows that to assist with weight maintenance, changes in lifestyle alone aren’t enough – the issue of increased hunger needs to be addressed.


Unfortunately there are few drugs that can suppress the appetite.

Phentermine (Duromine), a very old drug, was never properly studied when it was released around 50 years ago, so the safety of its long-term use remains unknown. Orlistat (Xenical) reduces fat absorption and may help with weight loss, but does not address the hunger.

There are other drugs and hormones that are currently undergoing evaluation but these may take several more years to become available.

In this gloomy picture for the obese patient, weight-loss surgery is currently the only treatment that has been demonstrated to result in long-term weight loss.

Weight-loss surgery

Three types of bariatric surgery operations are currently performed in Australia. Each suppresses hunger through different mechanisms:

  • Gastric banding sends a signal to the brain that the stomach is full.

  • Sleeve gastrectomy removes most of the stomach, which lowers the hunger hormone, ghrelin.

  • Roux-en-Y bypass delivers semi-digested food to the lower small bowel, raising the levels of appetite-suppressing hormones PYY and GLP-1.

Each operation has its benefits and risks. Gastric banding has the lowest rates of complications during the operation, but requires the most intensive follow up later on.

Sleeve gastrectomy is a new procedure and its long term durability remains unknown.

And Roux-en-Y has the highest operative risk but is easier to manage after surgery and gives patients the best chance to eliminate their type 2 diabetes.

But weight loss surgery isn’t suitable for all obese patients – it should be only considered by those who are severely obese, with a [body mass index]( (BMI) of 40 or above, or those with a BMI of 35 who have severe complications such as diabetes or sleep apnoea.

Given the difficulty with which the clinically obese can lose weight and keep it off, we must aim to prevent obesity from developing in the first place. Educating mothers about nutrition during pregnancy and in their child’s early years is a good place to start.

This is the eighth part of our series The science behind weight loss. To read the other instalments, follow the links below:

Part One: Diets and weight loss: separating facts from fiction
Part Two: Want to set up a weight loss scam? Here’s how…
Part Three: Feel manipulated? Anxious? Tune out the hype and learn to love your body
Part Four: Food v exercise: What makes the biggest difference in weight loss?
Part Five: An online tool to help achieve your weight-loss goal (no, it’s not a fad diet)
Part Six: Ignore the hype, real women don’t ‘bounce back’ to their pre-pregnant shape
Part Seven: Quick and easy, or painful and risky? The truth about liposuction
Part Nine: Are diet pills the silver bullet for obesity?
Part Ten: Want to try the latest fad diet? Just ask your local pharmacist

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